mmg_233_2013_genetics_genomicswikiaorg-20200214-history
Genome Wide Association Study for Susceptibility in Lung Adenocarcinoma
Introduction Lung cancer continues to be the leading cause of death worldwide and its incidence of occurence is rising not only in western countries, but all around the globe, specifically east Asia. Lung adenocarcinoma is a subset one of many classifications of lung cancer. It comprises nearly half of all lung cancers, smokers being at a higher risk than non-smokers. Even though the majority of patients who suffer from this form of lung cancer have been or are smokers, it is the most common type of cancer found in non-smokers as well. It is defined by its distinct histological features, molecular signatures, duct formation and production of excess amounts of mucus (1). Usually found centrally in the lungs, this differentiates itself from other forms of lung cancer such as small-cell lung cancer and squamous cell carcinoma, which are often located near or in the periphery of the lung (1). Genome Wide Association Studies Locating "at risk" Loci for People of Eastern Asian Ancestry Variations in TP63 and Its Association with Lung Adenocarcinoma Due to the rising occurence of lung adenocarcinoma in eastern Asian nations, a genome wide association study (GWAS) was conducted to observe any genetic factors that may play a risk in the inheritance of this disease. GWAS in lung cancer populations of eastern European ancestry identified the 15q24-25.1 region containing the most significant alterations (2) (3). Other loci were identified as having high risk within lung adenocarcinoma as well (5p15.33 and 6p21.33) (4) (5). These alterations have been refined to people of eastern European ancestry and associated with increased risk of acquiring lung adenocarcinoma. No other at risk loci had been observed in this GWAS or other similar independent studies. The allelic frequencies and strong inference of risk at these loci are very rare in Asian populations, especially 15q25. A GWAS was performed via two independent studies in Japanese and Korean individuals totaling 2,098 lung adenocarcinoma cases and 11,048 corresponding controls (6). Upon further investigation Miki et al., found that the SNP inside the TP63 gene region, rs10937405 was found to be varied in lung adenocarcinoma vs the control population. The GWAS revealed an OR of 1.27, Japanese populations OR of 1.29, Korean populations OR of 1.42 and a combined OR score of 1.31 for all studies (6). TP63 is a member of tumor suppressor TP53 family, involved in differentiation, response to stress and development. Accumulation of DNA damage and minimal response to cellular stress are certain to play a role in early tumorigenesis. Due to the location of SNP rs10937405 in intron 1 of the TP63 gene region, this indicates it may have a functional role in the transcription of the TP63 gene (6) . Also found in this study was an SNP rs2736100 in the TERT gene region. The reported OR values were very similar to that of the TP63 SNP, with a combined OR of 1.27 (6). TERT is the gene that encodes for telomerase reverse transcriptase, and responsible for lengthening telomere ends. This process allows cells that have reached senescence to avoid apoptosis and potentially become immortal, a significant process in cancer progression (7). Even though these two SNPs identified do not meet statistical significance, when presented together, they yield an OR of 4.13, with a statistically significant p-value (6). Mutations in the TERT Gene Region Contribute at risk Loci in Asian Populations Due to the aforementioned lack of SNP identification in Asian peoples, a study was conducted to confirm the findings suggested in other lung adenocarcinoma GWAS. Shiraishi et al., conduced a GWAS that confirmed the Miki et. al. report of SNPs located within the TERT and TP63 gene regions, although determined another significant SNP in TERT as well as mutated regions within genes BPTF and BTNL2 (8). This GWAS consisted of 6,029 individuals with lung adenocarcinoma and 13,535 corresponding controls, strictly of Japanese peoples. SNP rs2853677 in the TERT gene region yielded a total OR value of 1.41 and has a statistically significant p-value (8). SNP rs7216064 in intron 9 of the gene BPTF yielded a combined OR of 1.20, and SNP rs3817963 in the BTNL2 gene displayed a combined OR value of 1.18 (8). BPTF, nucleosome-remodeling factor subunit, is a protein thought to play a role in chromatin remodeling and also contains domains characteristic of proteins that regulate transcription during proliferation (9). BTNL2 is a protein that has been implicated in negatively regulating T-cell proliferation by the induction of pro-inflammatory cytokines such as TNF and IL-1 beta (10). Taken together as whole, these new insights into at risk loci for lung adenocarcinoma may help elucidate some of cultural differences in mechanism of action. References #http://en.wikipedia.org/wiki/Adenocarcinoma_of_the_lung #Hung RJ, et al. (2008) A susceptibility locus for lung cancer maps to nicotinic acetylcholine receptor subunit genes on 15q25. Nature 452(7187):633-637. #Amos CI, et al. (2008) Genome-wide association scan of tag SNPs identifies a susceptibility locus for lung cancer at 15q25.1. Nat Genet 40(5):616-622. #McKay JD, et al. (2008) Lung cancer susceptibility locus at 5p15.33. Nat Genet 40(12):1404-1406 #Wang Y, et al. (2008) Common 5p15.33 and 6p21.33 variants influence lung cancer risk. Nat Genet 40(12):1407-1409. #Miki D, et al. (2010) Variation in TP63 is associated with lung adenocarcinoma susceptibility in Japanese and Korean populations. Nature Genetics 42(10):893. #http://en.wikipedia.org/wiki/Telomerase_reverse_transcriptase #Shiraishi K, et al. (2012) A genome-wide association study identifies two new susceptibility loci for lung adenocarcinoma in the Japanese population. Nature genetics 44(8):900-903. #http://en.wikipedia.org/wiki/BPTF #http://www.genecards.org/cgi-bin/carddisp.pl?gene=BTNL2